Clinical diagnosis of cyanide poisoning is complicated by the lack of an easy, convenient assay for cyanide concentration in a patient. Therapy may be delayed with an unconfirmed diagnosis because the conventional antidote to cyanide poisoning exposes patients to substantial risks. Where the patient is not suffering from cyanide poisoning, administration of the antidote may cause patient death. However, delay in treatment may also result in patient death. The present invention is related to a means of diagnosing cyanide poisoning.
Molecules of oxygen enter the body through the respiratory organs and are transported to cells by the blood (oxyhemoglobin). The oxygen is used by cell organelles in the process of releasing energy from glucose molecules with the energy made available being used for a variety of cell activities. A continuing supply of oxygen is necessary for cell survival, and ultimately for the survival of an organism. Cyanide binds to the intracellular proteins (cytochromes) responsible for cellular respiration. Inhibition of cellular respiration by cyanide causes cell death by depriving cells of the ability to use oxygen.
Hemoglobin has a complex molecular structure that consists of two portions, heme and globin. The heme portion contains four atoms of iron, each of which can combine loosely with an oxygen molecule, forming oxyhemoglobin. The amount of oxygen that combines is determined by the concentration of oxygen. Because the chemical bonds that form between oxygen and hemoglobin are relatively unstable, oxygen is released from the hemoglobin molecule as the concentration of oxygen decreases. The oxygen can then diffuse from the blood into nearby cells. This necessary oxygen supply can be compromised by the presence of the CN.sup.- ion.
Oral ingestion of cyanogenic plants such as Cassava plants and apricot or peach seeds; cutaneous absorption; inhalation of smoke or industrial fumes and the breakdown of sodium nitroprusside can all introduce the CN.sup.- ion into the blood stream. Methemoglobin is a naturally occurring breakdown product of hemoglobin, which usually occurs in low concentrations in normal blood. While methemoglobin does not normally function to carry oxygen, it has increased affinity for CN.sup.- (the cyanide ion), and thus can scavenge CN.sup.- preferentially over normal hemoglobin.
Several methods of treating cyanide poisoning are known to those skilled in the art. One such method converts endogenous hemoglobin to methemoglobin with sodium nitrite. The methemoglobin removes cyanide ions from the various tissues and couples with them to become cyanomethemoglobin, a compound having relatively low toxicity. The bound CN is then excreted in the urine or retained until natural elimination can catabolize it. Sodium nitrite is, however, associated with hypotension which can be severe in hypovolemic patients. Additionally, the methemoglobinemia produced by sodium nitrite can also significantly decrease oxygen delivery and worsen tissue hypoxia in patients already compromised by coexisting carbon monoxide poisoning.
A second method of CN detoxification enhances the natural elimination pathway. The natural elimination pathway reacts CN with disulfide bonds to form thiocyanate endogenously, which can then be excreted in the urine. The enzymes responsible for this reaction have not been completely described, however, a primary one is rhodanese located mainly in the liver. During natural elimination, the disulfide bonds come from the body's sulfur-sulfane pool and include thiosulfate. To assist natural elimination a compound such as sodium thiosulfate or methylene blue (tetramethylthionine chloride) is administered, and aids in the conversion of cyanide to thiocyanate. Administration of exogenous thiosulfate is believed safe and effective. However, given alone, this type of compound acts too slowly for acute, critically ill patients.
The standard cyanide antidotal therapy in the United States (Taylor Pharmaceuticals, San Clemente, Calif.) is designed for pure cyanide poisoning and employs both thiosulfate and nitrites to induce methemoglobin formation from endogenous hemoglobin, thereby decreasing oxygen carrying capacity in the blood. This therapy includes administration of amyl nitrite, sodium nitrite and sodium thiosulfate. Amyl nitrate is applied by opening an ampule and holding it in front of the patients mouth for approximately 15 seconds. After a 15 second rest, the ampule is again placed in front of the patients mouth. This cycle is repeated until sodium nitrite can be administered. 300 mg of sodium nitrite is administered intravenously (10 milliliters in three percent solution) at a rate of 2.5 to 5 ml/min. The recommended dose of sodium nitrite for children is 6 to 8 ml/square meter (approximately 0.2 ml/kg of body weight) but is not to exceed 10 ml. Sodium thiosulfate is then injected. The dosage for adults is 12.5 grams of sodium thiosulfate (50 milliliters of 25 percent solution). The dosage for children is 7 g/square meter of body surface area, but dosage should not exceed 12.5 grams. Where the poison is taken by mouth, gastric lavage is performed, either concurrently with the above listed treatments by a third person or after administration of the above listed treatments. Given the risks associated with known treatments for cyanide poisoning, there exists a need for a noninvasive means of treating this condition that is of lower risk to the patient.
Prior to implementation of treatment, particularly when the treatment itself is of high risk, a diagnosis of the condition must be determined. While the physiological effects of cyanide poisoning are well known, the clinical diagnosis is often complicated by nonspecific symptoms and the lack of an easy, convenient assay for cyanide concentration in the blood. Methods known in the art for determining cyanide levels in blood generally involve acidification of the sample and trapping the resultant HCN gas into an alkali solution. The trap solution is then quantitated through a means such as chemical color change, potentiometry, chromatography or polarography. None of the existing procedures for the quantitation of cyanide levels in serum are rapid or available enough to alter therapeutic decisions, most require special expertise or equipment. In many hospitals, a cyanide assay can take hours to days or may not be available at all. In the absence of a laboratory test for cyanide, the diagnosis of acute toxicity is usually made from patient history and physical examination, which may be nonspecific
Cyanide poisoning can be rapidly fatal. Patients with severe poisoning may only survive a brief time. Thus, for effective treatment, antidote administration should occur as quickly as possible. However, in light of the substantial risks associated with known treatments for cyanide poisoning, therapy may be delayed because of diagnosis uncertainty. There thus exists a need for an accurate and rapid means of confirming cyanide poisoning.